Treatment agents, such as medicines, are generally administered to the body by various methods, such as topical application, oral ingestion, intravascular, intramuscular or parenteral injection and, less commonly, by aerosol insufflation and by transdermal iontophoresis. In all of these treatments there is an immediate dilution effect greatly reducing the concentration of the agent to which the target tissues or cells are exposed. Also, medicines administered by these systems may be more vulnerable to processes such as metabolic degradation, inactivation by binding to plasma proteins or accelerated clearance from the body. These processes adversely affect the drug's concentration and residence time in the target tissues and reduce its therapeutic efficacy.
Most of the above modes of drug administration also expose non-target tissues, i.e. those that do not require treatment, to the action of the drugs, with the consequent risk of serious side effects. It is this risk towards non-target tissues that reduces a drug's efficacy by restricting systemic concentrations to a threshold level above which side effects would become unacceptable.
Local drug delivery procedures can obviate some of the metabolic breakdown, early clearance and side effect problems affecting efficacy by presenting therapeutic concentrations of a drug only to the target site, minimizing effects upon non-target tissues. The reduction in quantity of a drug required minimizes side effects and can also result in lower treatment costs.
Recognition of the advantages of local delivery strategies has stimulated the development of a number of catheter-based delivery devices which apply drugs directly to the body tissues at specific locations, often to sites that would be otherwise inaccessible without surgery. However, if the specific target for an agent is intracellular, simple local application of the drug, followed by its passive diffusion into tissues, does not facilitate movement of the drug across cell surface membrane barriers into intracellular compartments. Diffusion away from the target cells occurs and high extracellular concentrations are rarely sustained long enough to mediate significant passage into the cells. Some drugs penetrate intact cell membranes by diffusion only very poorly and may require specific carrier or bulk transport by a phagocytic or pinocytic mechanism, to penetrate the cell membrane. These natural transport systems operate inefficiently, or not at all, when the tissues are affected by disease.
Double balloon catheters have been used to confine a drug solution to a specific segment of a blood vessel requiring treatment. For this use, internal lumens in the catheter are needed to transport the liquid drug to the isolated compartment and to evacuate any remaining drug after treatment. Apart from the dangers in occluding blood flow with the balloons and the associated ischaemic risk, any downstream leakage due to defective balloon sealing can also result in overdosing of the drug. Moreover, much drug can be lost through side branches arising from the vessel in the isolated segment between the balloons.
Devices have also been developed to try to improve the depth of penetration into tissue by pressure driving a solution of the drug into the vessel wall via tiny orifices in the fabric of a balloon. There is, however, some evidence that high pressure "jetting" of a drug solution out of small pores close to the vessel lumen can in fact cause vessel wall injury. The development of double skinned, microporous (or weeping) balloons obviated this "jetting" effect to some extent, but diffusion of the drug into the vessel wall is still slow, and much of the drug can be lost through subsequent "washout effects".
Iontophoretic catheters have been used in some animal angioplasty studies to provide an electrical driving force for movement of a drug into tissues. This technique requires that the agent to be delivered carries an electrical charge under the local physiological pH conditions. While iontophoresis does enhance the delivery of drugs into body tissues, it has been shown in transdermal iontophoresis ("TDI"), that migration of drugs through skin predominantly occurs via extracellular pathways (sweat glands and hair follicle channels) where the current densities are much higher than elsewhere. This preferential channel movement can be favorable towards providing high drug concentrations in the skin capillary bed and onward into the circulation. However, with other tissues, such as blood vessels, the delivery of drugs to the vessel wall cells will be of low efficiency.
Angioplasty procedures generally involve the introduction of a small balloon catheter into the femoral artery in a patient's leg and, with the help of a guide wire, the catheter is passed by remote manipulation under fluoroscopy into the heart. The balloon can then be positioned in a region of a coronary artery that has become constricted due to atherosclerosis and by inflating and deflating the balloon several times the bore of the diseased artery is mechanically widened until a satisfactory blood flow through the vessel has been restored. If the artery is severely damaged by disease, and perhaps hardened by calcium deposition, this balloon inflation may also cause some degree of additional injury with local de-endothelialisation and exposure of underlying extracellular matrix components such as collagen and elastin. In a few patients excessive recruitment of platelets and fibrinogen can then result in an acute thrombotic occlusion. This is now less common, however, with the routine use of heparin and aspirin cover during the angioplasty procedure.
Generally, angioplasty procedures produce excellent results obviating the need for bypass surgery, but in about 30-40% of patients, an ostensibly successful initial dilatation of the artery may be followed by a renarrowing of the vessel (restenosis) some 3 to 9 months later. If this restenosis is severe, these patients may require a second angioplasty procedure, often with implantation of a stent to act as a scaffold in the vessel. In other cases arterial reconstruction under by-pass surgery, which is a higher risk procedure, may be required. With more than 800,000 PTCA procedures now performed world-wide annually, the socio-economic implication of this 30-40% restenosis rate has become a matter of serious concern to interventional cardiologists.
The pathophysiology of this late restenosis is complex, and involves a wide range of cellular and molecular responses, many of which are not yet fully understood. Although a number of putative targets for drug interference have been identified, more than 50 clinical trials (some large and multi-center) with a wide range of different drugs have failed to reveal a satisfactory pharmacotherapeutic approach to reducing the incidence of restenosis. One problem is that for some of the potentially useful drugs, it is not possible by systemic administration to get a therapeutically effective level of the drug in the vessel wall tissue without significantly affecting non-target tissues elsewhere.
Accordingly, what is needed are devices for delivering treatment agents to specific locations, including intracellular locations in a safe and effective manner. These devices would deliver the agents to a diseased site in effective amounts without endangering normal tissues or cells and thus reduce or prevent the occurrence of undesirable side effects.